Compositions and methods for enhancing the efficacy of contraceptive microbicides

ABSTRACT

The present disclosure relates to compositions and methods for contraception that also enhance the efficacy of microbicides. Such compositions serve the dual purpose of preventing pregnancy and lessening the risk of spreading sexually transmitted diseases. More specifically, the compositions and methods relate to syngergistic contraceptive microbicide and antiviral compositions comprising a combination of a contraceptive microbicide and an antiviral agent in an acidic carrier that enhances the efficacy of both the contraceptive microbicide and antiviral agent.

TECHNICAL FIELD

The present disclosure relates to compositions and methods forcontraception that also enhance the efficacy of microbicides. Suchcompositions serve the dual purpose of preventing pregnancy andlessening the risk of spreading sexually transmitted diseases.

BACKGROUND OF INVENTION

Human immunodeficiency virus (HIV), the etiologic agent of acquiredimmunodeficiency syndrome (AIDS) is the fastest growing cause of deathin women of reproductive age. Worldwide, the heterosexual transmissionof AIDS is the prevalent mode of transmission of AIDS, accounting forabout 90% of all HIV infections in women. Therefore, significantattention has been directed to investigating measures that block sexualspreading of HIV infection. As there is no effective treatment orvaccine against AIDS, preventive measures are the primary tools that canpresently reduce transmission of HIV. For example, the consistent andcorrect use of condoms represents an effective barrier to prevent HIVtransmission. However, the risk of acquiring infection can only besignificantly reduced if condoms are used for almost all sexualintercourse in HIV prevalent communities; a result that can not beachieved despite intensive prevention programs to increase condom use.

Significant emphasis has been placed on the development of intravaginalmicrobicidal agents capable of preventing and/or reducing the spread ofa variety of sexually transmitted diseases (STDs) in addition to HerpesSimplex Virus (HSV) and HIV. The development of microbicides for topicaluse represents an important alternative to condom usage. A microbicideis any agent that kills or deactivates disease-causing microbes,including viruses. According to the International Association ofPhysicians in AIDS CARE (IAPAC), the definition of microbicides alsoincludes interventions that can block or prevent infection, as well asamplification of the body's natural defenses to prevent infectionthrough sexual acts.

Ideally, microbicides should have little or no side effects at aneffective microbicidal concentration. Accordingly, the drug used as amicrobicide should have little or no immunosuppressive activity at aneffective microbicidal concentration. In addition, the ideal microbicideshould sufficiently withstand varying temperatures and acceptablyfunction within varied pH ranges (ranges of alkaline and acidic levelsin the vagina). Further, it should not eliminate the natural beneficiallactobacilli that reside in the vagina and contribute to vaginal health.

Topical microbicides would be even more beneficial if they also hadcontraceptive capabilities. Contraception is also important for womenwith STDs to prevent transmitting diseases to future generation,especially since many women with STDs are of childbearing age. Atpresent, a majority of commercially available dual-purpose spermicidalmicrobicides have detergent ingredients that disrupt cell membranes. Themost widely used vaginal spermicide, nonoxynol-9 (N-9), because of itsmembrane disruptive properties, has been shown to damage thecervicovaginal epithelium, cause an acute inflammatory tissue response,alter vaginal microflora, and enhance the risk of promotingopportunistic infections in the genitourinary tract. N-9 is also toxicto vaginal and cervical cells which increases the permeability ofvaginal tissue. It can also kill the Lactobacillus sp. that populate thevaginal tract and are generally regarded as beneficial. Lactobacillusproduce lactic acid and hydrogen peroxide, which helps maintain theacidic pH of the vagina (˜pH 3.5 to 5.0) and a healthy vaginal flora. Atthis pH, a number of STD-causing organisms like HIV are inactivated.

Other spermicidal microbicides in the form of vaginal creams andointments are currently available over the counter or by prescription.Still others are in various stages of development. Examples includeoctoxynol-9 and benzalkonium chloride. Gels designed to control vaginalpH are also available, such as AciJel™ (Ortho-McNeil PharmaceuticalCorp., Raritan, N.J.) which is a water dispersible buffered gel having apH of 3.9 to 4.1. It is used to restore and maintain normal vaginalacidity. Such gels are designed to control vaginal pH and are notspecifically designed to prevent STDs and/or contraception, and thus donot always possess effective microbicidal activity.

As discussed, presently marketed vaginal contraceptive compositions,often containing N-9 as an active ingredient, are generally known in theart. While presently marketed vaginal contraceptive formulations aid inpreventing pregnancy, their ability to effectively prevent STDs,particularly HIV/AIDS, is very limited. Moreover, recent analyses showthat N-9, when used frequently by women at high risk may actuallyincrease the risk of HIV infection (WHO 2002, WHO/CONRAD technicalconsultation on nonoxynol-9, Geneva).

Additionally, several microbicides under development containanti-retroviral agents that had originally been developed for thetreatment of patients with HIV infection. However, only temporary andlimited benefits are observed in HIV-infected patients treated with anyof the actual anti-retrovirals or combinations thereof. The limitedability of these agents to decrease viral burden, the rapid developmentof resistance and the toxic side-effects of most drugs has limited theirlong-term efficacy. One major problem associated with the administrationof antiviral agents to patients is their poor ability to penetrate andtarget infected cells. Rapid drug clearance and the toxicity of parentcompounds or metabolites also constitute some of the major drawbacksthat may slow down the development and use of many antiviral agents.Given the severe toxicity of antiviral agents actually available totreat AIDS and other viral diseases and their limited ability to targetinfected cells, strategies aimed at reaching therapeutic levels of drugsinto infected cells and reducing toxicity is needed.

One of the more recently studied antimicrobials is BufferGel™ (ReProtectLLC, Baltimore, Md.), which has undergone clinical trials. It is anegatively charged, non-absorbable, high molecular weight polymer gelthat is designed to maintain vaginal pH below 5 in the presence ofsemen. As detailed in U.S. Pat. No. 5,617,877, BufferGel™ is formulatedfrom a polymer comprised of carboxylated monomers. The polymers havebuffering capacity which help control the vaginal pH. However, forcontraceptive purposes, BufferGel™ is designed to be used with a deviceto be inserted into the vagina and positioned over the cervix. As such,to be effective, the device must remain in position over the cervix.Removal of the device or a shift of its position relative to the cervixcan destroy, or at least significantly reduce, its effectiveness.

Recent studies have shown that a significant contribution to theantimicrobial properties naturally present in the vagina is primarilydue to the microbicidal activity of the lactic acid molecule, and is notnecessarily due to low pH alone or to the presence of hydrogen peroxide.(O'Hanlon et al., BMC Infect Dis., 11:200, 2011). In particular, it hasbeen shown that in vaginal fluid, bacteria associated with bacterialvaginosis can be suppressed with lactic acid, but to a much lesserextent with other acids at the same pH.

Accordingly, there is a need for dual purpose contraceptive microbicideand antiviral compositions and methods that provide improvedcontraceptive and microbicidal activity in order to prevent or reducethe risk of transmission of STDs, including HIV and HSV-2 whilesimultaneously preventing unwanted pregnancies. Such compositions shouldbe useful for vaginal administration in effective doses that do notinactivate Lactobacillus sp. or cause overt vaginal irritation or othertoxicity.

SUMMARY OF INVENTION

The embodiments disclosed below satisfy this need. The followingsimplified summary is provided in order to establish a basicunderstanding of some aspects of the claimed subject matter. Thissummary is not an extensive overview, and is not intended to identifykey/critical elements or to delineate the scope of the claimed subjectmatter.

In an exemplary embodiment, the present disclosure is directed tocontraceptive microbicide and antiviral compositions and methods of usethereof, such compositions including: (a) an effective amount of abioadhesive (wherein the bioadhesive includes (i) a matrix-formingcompound; (ii) a bioadhesive compound that may be the same or differentfrom the matrix-forming compound; and (iii) lactic acid); (b)1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid, or aphysiologically functional derivative thereof; and (c) apharmaceutically acceptable carrier. In various embodiments, suchcompositions generally have a pH of 5.0 or below, and in furtherembodiments, such compositions are not in a matrix state until they comein contact with ejaculate. In other embodiments, the lactic acid isL-lactic acid.

In additional embodiments of the present disclosure, the compositionsmay also include a humectant and/or a preservative.

In another embodiment, the present disclosure is directed tocontraceptive microbicide and antiviral compositions and methods of usethereof, such compositions including: (a) a matrix-forming compound; (b)a bioadhesive compound that may be the same or different from thematrix-forming compound; (c) lactic acid; (d)1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid or aphysiologically functional derivative thereof; and (e) apharmaceutically acceptable carrier. In various embodiments, suchcompositions generally have a pH of 5.0 or below, and in furtherembodiments, the compositions have buffering capabilities such that thepH is maintained below 5.0 in the presence of a normal amount ofejaculate.

Other aspects of the disclosure are found throughout the specification.

DETAILED DESCRIPTION OF INVENTION

Disclosed herein are compositions and methods for contraception thatalso enhance the efficacy of microbicides. Such compositions serve thedual purpose of preventing pregnancy and lessening the risk of spreadingsexually transmitted diseases. More specifically, the compositions andmethods disclosed herein relate to synergistic contraceptive microbicideand antiviral compositions comprising a combination of a contraceptivemicrobicide and an antiviral agent in an acidic carrier that enhancesthe efficacy of both the contraceptive microbicide and antiviral agent.

To facilitate understanding of the disclosure that follows, a number ofterms are defined below.

When the terms “one,” “a,” “an” are used in this disclosure, they mean“at least one” or “one or more,” unless otherwise indicated.

As used herein, the terms “microbicide” and “microbicidal” refer to acompound capable of preventing or inhibiting the growth and/orpreventing or reducing the infectivity of microbes, including viruses,bacteria, fungi and algae.

As used herein, the term “sexually transmitted disease” is usedinterchangeably with “STD,” “sexually transmitted infection,” “STI”and/or the plural thereof. An STD is an illness or pathophysiologicalcondition that has a significant probability of transmission betweenhumans by means of any form of sexual contact, including kissing. Theterm STD may also encompass a person who is infected, and maypotentially infect others, without showing signs of disease orinfection.

The terms “synergy” and “synergistic” mean that the effect achieved withthe compounds used together is greater than the sum of the effects thatresults from using the compounds separately, i.e. greater than whatwould be predicted based on the two active ingredients administeredseparately. A synergistic effect may be attained when the compounds are:(1) co-formulated and administered or delivered simultaneously in acombined formulation; (2) delivered by alternation or in parallel asseparate formulations; or (3) by some other regimen. A synergisticantiviral effect denotes an antiviral effect which is greater than thepredicted purely additive effects of the individual compounds of thecombination.

As used herein, the term “physiologically functional derivative” refersto a pharmaceutically active compound with equivalent or near equivalentphysiological functionality to Acidform or tenofovir when administeredin combination with another pharmaceutically active compound in acombination of the disclosure. As used herein, the term “physiologicallyfunctional derivative” includes any: physiologically acceptable salt,ether, ester, prodrug, solvate, stereoisomer including enantiomer,diastereomer or stereoisomerically enriched or racemic mixture, and anyother compound which upon administration to the recipient, is capable ofproviding (directly or indirectly) such a compound or anantiviral-active metabolite or residue thereof.

As used herein, the term “contacting” refers to any suitable method ofbringing one or more of the contraceptive microbicide and antiviralcompounds described herein into contact with a sexually-transmitted orsexually-acquired microbe or microbial cell, as described herein. Invitro or ex vivo, this is achieved by exposing the microbe or microbialcell to the microbicide in a suitable medium. For exemplary in vivoapplications, topical methods of administration are suitable asdescribed herein.

As used herein, the term “matrix” is meant to refer to a plurality ofdifferent molecules that form a three-dimensional structure via ionicinteractions there between.

The term “pH of 4 or below” means a pH that is less than 4.5.

The term “buffering capabilities” means the ability to maintain adesired pH when contacted with a compound having a different pH. Inparticular, buffering capabilities means the ability to maintain ahealthy vaginal pH in the presence of normal amounts of ejaculate.

The term “contacted with ejaculate” means the presence of semen in thevolume normally occurring during ejaculation, e.g., between 0.1 to 11milliliters (Rehan, et al., Fertil Steril. 1975, 26:492-502).

The contraceptive microbicide and antiviral compositions and methodsdisclosed prevent or reduce the risk of the transmission of STDs and/orcommon vaginal infections. STDs include, but are not limited to,HIV/AIDS, herpes (caused by herpes simplex virus type 1 (HSV-1) orherpes simplex virus type 2 (HSV-2), gonorrhea, chlamydia, syphilis, andtrichomoniasis. Non-limiting examples of common vaginal infectionsinclude bacterial vaginosis (BV) and vaginal candidiasis. Similarcompositions and methods of application of such compositions, asdescribed herein, can be used for preventing or treating STDs and/orcommon vaginal infections.

The compositions of the present disclosure comprise a combination of abioadhesive agent with contraceptive and microbicidal properties (i.e. a“contraceptive microbcide”) and a particular antiviral agent, tenofovir.The contraceptive microbicide has bioadhesive properties and bufferingcapabilities. Upon contact with semen, the contraceptive microbicideforms a matrix that traps the sperm, and the buffering capabilities keepthe pH at a low level further inactivating the sperm. Tenofovir is anantiretroviral drug designed to inhibit reverse transcriptase. Theprodrug form of tenofovir, tenofovir disproxyl fumarate, has beenapproved by the U.S. Food and Drug Administration for treating HIV andchronic hepatitis B and may be effective against other viruses such asherpes. (Andrei, et al., Cell Host Microbe., 10:379-89, 2011). Inexemplary embodiments, a synergistic effect is achieved between the twocomponents. More particularly, the negatively charged monophosphatemoiety of tenofovir forms ionic interactions with the matrix formingagent and/or bioadhesive compound, which is further enhanced by lacticacid. When the matrix is formed, it facilitates prolonged release of thetenofovir, thus enhancing efficacy.

It is further believed that the compositions of the present disclosureexhibit improved efficacy because the tenofovir concentration ismaintained between effective and toxic levels, due to the fact that thematrix formation and bioadhesive properties inhibit the dilution of thedrug away from the delivery point, thereby improving targeting andlocalization of the drug. In this context, bioadhesion increases theintimacy and duration of contact between the tenofovir and the mucosalsurface. The combined effects of this enhanced, direct drug absorption,and the decrease in excretion rate that results from reduced diffusionand improved localization significantly enhances bioavailability of thedrug and allows for a smaller dosage and less frequent administration.

Tenofovir (Gilead Science, Inc.)

Tenofovir, which includes derivatives, analogues, prodrugs and saltsthereof, belongs to a class of antiretroviral drugs known as nucleotideanalogue reverse transcriptase inhibitors (NtRTIs), which block reversetranscriptase. It has the chemical name1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid [CAS Registrynumber: 147127-20-6]. The structure of tenofovir is shown below:

Tenofovir is a competitive inhibitor of other naturally occurringnucleotides, and its ultimate biological activity is viral DNA chaintermination. Tenofovir is a novel nucleotide analog with antiviralactivity against both HIV and Hepatitis B. The mechanism of tenofovir issimilar to that of nucleoside analogs, which interferes with reversetranscriptase and prevents translation of viral genetic material intoviral DNA. Unlike the nucleoside analogs, the NtRTIs are chemicallypre-activated with the presence of a phosphate group. Since thephosphorylation step is not necessary, nucleotide analogs canincorporate into viral DNA chain more rapidly than nucleoside analogs.More importantly, this will bypass a viral mechanism of nucleosideresistance.

Contraceptive Microbicide

In one embodiment, the contractive microbicide is Acidform (also knownas Amphora® (U.S. Pat. No. 6,706,276, WO 01/66084), which is a gel that,when placed in a body orifice (e.g., vagina), forms a matrix uponcontact with ejaculate and thus entraps and inactivates spermatozoaand/or STD and STI-causing microbes. In one general embodiment, thecontraceptive microbicide contains (1) a matrix-forming compound, (2) abioadhesive compound, and (3) lactic acid. Some compounds, such aschitosan, can act as both the matrix-forming compound and thebioadhesive compound.

In exemplary embodiments, the Acidform used generally contains (1) about1-10% of one or more matrix-forming compounds, (2) about 1-10% of one ormore bioadhesive compounds, and (3) about 1-10% of lactic acid. In otherembodiments of, the Acidform composition contains (1) about 3-5% of oneor more matrix-forming compounds, (2) about 2.5-6% of one or morebioadhesive compounds, and (3) about 1-7% of lactic acid. In otherembodiments, the Acidform composition contains (1) about 3.5-4.5% of oneor more matrix-forming compounds, (2) about 2.5-3.5% of one or morebioadhesive compounds, and (3) about 1-4% of lactic acid.

In other exemplary embodiment, the Acidform used generally contains (1)about 1-10% of one or more matrix-forming compounds, (2) about 1-10% ofone or more bioadhesive compounds, and (3) about 1-10% of L-lactic acid.In other embodiments, the Acidform composition contains (1) about 3-5%of one or more matrix-forming compounds, (2) about 2.5-6% of one or morebioadhesive compounds, and (3) about 1-7% of L-lactic acid. In otherembodiments, the Acidform composition contains (1) about 3.5-4.5% of oneor more matrix-forming compounds, (2) about 2.5-3.5% of one or morebioadhesive compounds, and (3) about 1-4% of L-lactic acid.

Matrix-forming compounds suitable for use in the present disclosureshould be stable over a wide pH range, especially over the normal acidicpH values found in the vagina. Suitable matrix-forming compoundsinclude, for example, alginic acid, chitosan, gellan gum, poloxamer, andthe like. Alginic acid is a generally linear glycouronan polymercontaining a mixture of −(1,4)-D-gulosyuronic acid and−(1,4)-D-gulosyuronic acid residues. Generally, the molecular weight ofthe alginic acid is the range of about 20,000 to about 300,000 g/mole,in other embodiments in the range of about 20,000 to about 250,000g/mole, and in further embodiments about 240,000 g/mole. Alginic acid isexpected to form insoluble alginates by interacting with monovalent anddivalent cations (especially Na⁺, K⁺, and Ca⁺⁺) in seminal plasma. Sincevaginal fluids generally contain very little Ca⁺⁺, the semisolid matrixis formed only when ejaculate is present. In such cases, the semisolidmatrix will trap STD-causing microbes and spermatozoa so that theycannot migrate through the lower female genital tract. Alginates alsoswell in contact with water, thereby assisting in maintaining thedesired gel or matrix structure within the vagina. Of course, alginicacid or salts of alginic acid may also contribute to the acid bufferingactivity of Acidform since they have a pH of about 1.5 to about 3.5 inan aqueous solution. Furthermore, alginic acid may also contribute tothe bioadhesive nature of the present formulations and, therefore,assist in providing bioadhesive activity. Because of its high molecularweight, alginic acid will not be absorbed by the body. Thus, itsmatrix-forming, bioadhesive, and acid-buffering properties will bemaintained so as long as the gel remains in the vagina. Moreover, due tothe innate bioadhesive properties of the trapping gel, it will normallyremain within the vagina for about 12 to 24 hours (or even longer) ifnot removed by the woman.

Bioadhesive compounds suitable for use in the present dislcosureinclude, for example, xanthan gum, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose,chitosan, polycarbophil, carbopol, and the like. In at least oneembodiment, the bioadhesive compound is xanthan gum, a high molecularweight polysaccharide gum containing D-glucosyl, D-mannosyl, andD-glucosyluronic acid residues and varying proportions of O-acetyl andpyruvic acid acetal. The primary structure is a cellulose backbone withtrisaccharide side chains; the repeating unit is a pentasaccharide.Generally, the molecular weight is greater than about 106 g/mole.

The contraceptive microbicide further comprises lactic acid or otherbuffering agents that act to maintain the pH of the vagina within itsnormal acidic range (i.e., a pH of less than about 5 and more preferablyin the range of about 3.5 to about 4.5) even in the presence of normalamounts of ejaculate. Besides lactic acid, suitable buffering agentsinclude, but are not limited to, for example, citric acid, potassiumacid tartrate, benzoic acid, alginic acid, sorbic acid, fumaric acid,ascorbic acid, stearic acid, oleic acid, tartaric acid, edetic acidethylenediaminetetracetic acid, acetic acid, malic acid, and the like.The acids may be added as free acids, hydrates, or pharmaceuticallyacceptable salts. Of course, the free acids can be converted to thecorresponding salts in situ (i.e., within the vagina). In variousexemplary embodiments, several buffering agents are included in theAcidform composition to provide increased buffering capacity. Alginicacid, of course, can function as both a matrix-forming agent and abuffering agent. Since alginic acid will not be absorbed by the body,its acid buffering effect will be longer lasting as compared to theother buffering agents which may be absorbed by the body.

Pharmaceutically Acceptable Carrier

In one embodiment, the pharmaceutical carrier is water. Otherpharmaceutically acceptable carriers that are suitable for vaginaldelivery are well know and can be used in place of water. One example ofa suitable pharmaceutically acceptable carrier is petrolatum, such aswhite petrolatum.

Optional Ingredients

Additional optional excipients that may be used in the compositions ofthe present disclosure may also include humectants. Suitable humectantsinclude, but are not limited to, for example, glycerol, polyethyleneglycols, propylene glycols, sorbitol, triacetin, and the like. In oneexemplary embodiment, glycerol is used to prevent the formation of a dryfilm on the gel when placed within the vagina. Glycerol may also act asa lubricant. Additionally, the compositions may also include apreservative. Suitable preservatives include, but are not limited to,for example, benzoic acid, sodium benzoate, methylparaben, ethylparaben,butylparaben, propylparaben, benzyalkonium chloride, phenylmercuricnitrate, chlorhexidine, and the like. In one exemplary embodiment,benzoic acid is used and may also contribute to the buffering capacityof the Acidform gel.

In one exemplary embodiment of the present disclosure, the contraceptivemicrobicide is further described as follows: the matrix-forming compoundis alginic acid; the bioadhesive compound is xanthan gum and/orhydroxycellulose; lactic acid is used or is substituted by citric acid,benzoic acid or potassium acid tartrate; glycerol is included as ahumectant; benzoic acid is used as a preservative; and water is thepharmaceutically acceptable carrier. In another embodiment, thecomposition contains xanthan gum, alginic acid, lactic acid, citricacid, benzoic acid, potassium bitartrate, glycerol, and water. Inanother embodiment, the lactic acid is L-lactic acid.

As discussed, lactic acid or other suitable buffering agents are used tomaintain the pH of the vagina within its normal acidic range (i.e., a pHof less than about 5 and more preferably in the range of about 3.5 toabout 4.5) even in the presence of normal amounts of ejaculate. Inparticular, it has been discovered that lactic acid significantlyincreases the microbicidal potency in relation to other natural vaginaldefense mechanisms, such as hydrogen peroxide. This feature waspreviously unknown to those of skill in the art, and the inventors ofthe present disclosure have surprisingly found that the contraceptivemicrobicide, when formulated using lactic acid as a buffering agent,possesses significantly greater microbicidal activity than formulationsthat do not use lactic acid as a buffering agent.

Specifically, the presence of lactic acid results in greaterinactivation of microbes, including viruses, in comparison to compoundssuch as hydrogen peroxide or acetic acid at equivalent pH. The mechanismof action by which lactic acid increases microbicidal potency isbelieved to be the disruption of the cell membranes of gram-negativebacteria, and also acts to inactivate HIV and HSV-2.

More specifically, lactic acid has two isomers, one is known asL-(+)-lactic acid or (S)-lactic acid and the other is D-(−)-lactic acidor (R)-lactic acid. Recent discovery has shown that the L form of lacticacid is more potent in inactivating HIV than D or racemic lactic acid.While the precise mechanism of how L-lactic acid invactivates HIV isunknown, the stereochemical dependent activity suggests that it acts onproteins. (Purcell et al., AIDS Res Hum Retroviruses. 2012November;28(11):1389-96.)

Lactic acid is produced by lactic acid bacteria such as Lactobacillusspecies. However, lactic acid bacteria generally produce both D and Llactic acid. Furthermore, lactic acid bacteria can be difficult to grow.Recombinant methods can be used to specifically manufacture L-lacticacid using hosts that easier to grow such as yeast or Escherichia coli.(Ishida et al., Appl Environ Microbiol. 2005 April; 71(4): 1961 1970 andDien et al., J Ind Microbiol Biotechnol. 2001 October;27(4):259-64.)Alternatively, purified L-lactic acid can be purchased from establishedchemical suppliers such as Sigma-Aldrich® (St. Louis, Miss.).

The pharmaceutical composition may be in the form of a gel, asemi-solid, a cream, and/or a lotion. Generally, the microbicide may beadministered as a topical ointment applied to the lining of the vaginaand/or cervix and/or rectum, which can be accomplished as a gel, cream,lotion, non-aqueous or aqueous solution used to flush the vaginal orrectal cavity, and/or a vaginal or rectal suppository. In otherembodiments, the contraceptive microbicide and antiviral composition maybe administered in a spray formulation. In addition, the contraceptivemicrobicide and antiviral compositions may be delivered usingmicrobicide-impregnated diaphragms and female and male condoms.

Furthermore, in addition to the contraceptive microbicide and antiviralcompositions disclosed herein, the balance of the compositions, i.e.,typically from about 0-10% weight, or from about 0.1-5% weight, or fromabout 0.1-3% weight, may optionally comprise one or more cosmeticingredients. Such cosmetic ingredients are known to those skilled in theart and are often referred to in the art as diluents, solvents, andadjuvants. Typically, cosmetic ingredients include, for example; water,ethyl alcohol, isopropyl alcohol, glycerin, glycerol propylene glycol,sorbitol, and other high molecular weight alcohols. In addition,contraceptive compositions may contain minor amounts of other additives,such as, for example; stabilizers, surfactants, menthol, eucalyptus oil,other essential oils, fragrances, and the like. The selection andamounts of cosmetic ingredients, other additives, and blendingprocedures can be carried out in accordance with techniques well-knownin the art.

In exemplary embodiments, the present disclosure involves the topicalapplication of contraceptive mcirobicide and antiviral compositions asdescribed herein. In the context of the present disclosure, it is to beunderstood that the term topical application includes application thebody cavities as well as to the skin. Thus, for example, theaforementioned compositions are applied to a body cavity such as thevagina, anus, rectum or mouth. Furthermore, the topical application maybe carried out before, during or after intercourse, or alternatively,carried out independent from intercourse.

It is to be understood that the contraceptive microbicide and antiviralcompositions of the present disclosure may be delivered to the vagina ofa mammal by any means known to those skilled in the art. Typical formsfor delivery of the compositions include, for example; creams, lotions,gels, foams, intervaginal devices such as sponges and suppositories, andfilms. In addition, the contraceptive microbicide and antiviralcompositions may be used as personal care products, such as, forexample, condom lubricants, and the like. Such lubricants may comprisecommonly known ingredients such as, for example: humectants, e.g.,glycerin, sorbitol, mannitol, glycols and glycol ethers; buffers, e.g.,glucono-d-lactone; germicides or bactericides, e.g., chlorhexidinegluconate; preservatives, e.g., methylparaben; viscosifiers, e.g.,hydroxyethyl cellulose, etc.; other adjuvants, e.g., colors andfragrances; in addition to the compositions of the present disclosure.Those skilled in the art will recognize that the physical properties,e.g., viscosity, of such delivery forms may vary widely. For example,the viscosity of a gel form of the composition of the presentdisclosure, e.g., 150,000 centipoise, may be substantially higher thanthe viscosity of lotion form of the composition of the presentdisclosure, e.g., 100 centipoise. Further details concerning thematerials, ingredients, pro-portions and procedures of such deliveryforms can be selected in accordance with techniques well-known in theart.

In various embodiments, the contraceptive mcirobicide and antiviralcompositions of the present disclosure are preferably administered tothe vagina of the mammal in a dosage which is effective to immobilizesperm present in the vagina and/or to inhibit their penetration incervical mucus. Typical dosages range between about 1-10 grams, orbetween 3-7 grams, or between 4-6 grams of the composition.

It will be readily apparent to those skilled in the art that othercompounds functioning as precursors, analogs and derivatives such assalts and esters of the present compounds can be utilized.

The disclosure set forth above is provided to give those of ordinaryskill in the art a complete disclosure and description of how to makeand use embodiments of the compositions and methods, and are notintended to limit the scope of what the inventors regard as theirinvention. Modifications of the above-described modes (for carrying outthe disclosure that are obvious to persons of skill in the art) areintended to be within the scope of the following claims. Allpublications, patents, and patent applications cited in thisspecification are incorporated herein by reference in their entirety asif each such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A contraceptive microbicide and antiviralcomposition comprising: (a) a contraceptive microbicide comprising: (i)a matrix-forming compound; (ii) a bioadhesive compound that may be thesame or different from the matrix-forming compound; and (iii) lacticacid; (b) 1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid or aphysiologically functional derivative thereof; and (c) an aqueous-basedpharmaceutically acceptable carrier; wherein the composition has a pH of4 or below; wherein the composition has buffering capabilities andmaintains a pH below neutral when contacted with ejaculate; wherein thethe composition is in a nonmatrix state until it comes in contact withejaculate: and wherein matrix formation enhances delivery of the1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid or aphysiologically functional derivative thereof by facilitating prolongedrelease.
 2. (canceled)
 3. The composition of claim 1, wherein thecomposition further comprises a humectant.
 4. The composition of claim1, wherein the composition further comprises a preservative.
 5. Thecomposition of claim 1, wherein the lactic acid is L-lactic acid.
 6. Acomposition comprising: (a) a matrix-forming compound; (b) a bioadhesivecompound that may be the same or different from the matrix-formingcompound; (c) lactic acid; (d)1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid or aphysiologically functional derivative thereof; and (e) an aqueous-basedpharmaceutically acceptable carrier; wherein the composition has a pH of5.0 or below; wherein the composition has buffering capabilities andmaintains a pH below 5.0 in the presence of normal amounts of ejaculate;wherein the composition is in a nonmatrix state until it comes incontact with ejaculate; and wherein matrix formation enhances deliveryof the 1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid or aphysiologically functional derivative thereof by facilitating prolongedrelease.
 7. A method for reducing the risk of spreading a sexuallytransmitted disease and preventing conception comprising administeringan effective amount of the composition according to claim
 1. 8. Thecomposition of claim 6, wherein the lactic acid is L-lactic acid.
 9. Thecomposition of claim 6, wherein the matrix forming compound is selectedfrom the group consisting of: alginic acid, chitosan, gellan gum, andpoloxamer.
 10. The composition of claim 9, wherein the matrix formingcompound is alginic acid.
 11. The composition of claim 6, wherein thebioadhesive compound is selected from the group consisting of: xanthangum, alginic acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, chitosan, polycarbophil, andcarbopol.
 12. The composition of claim 11, wherein the bioadhesivecompound is xanthan gum.
 13. A composition comprising: (a) amatrix-forming compound selected from the group consisting of: alginicacid, chitosan, gellan gum, and poloxamer; (b) a bioadhesive compoundselected from the group consisting of: xanthan gum, hydroxypropylcellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, chitosan, polycarbophil, and carbopol; (c) lactic acid; (d)1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid or aphysiologically functional derivative thereof; and (e) an aqueous basedpharmaceutically acceptable carrier; wherein the composition has a pH of5.0 or below; wherein the composition maintains a pH of 5.0 or below inthe presence of normal amounts of ejaculate; wherein the composition isin a nonmatrix state until it comes in contact with ejaculate; andwherein matrix formation enhances delivery of the1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid or aphysiologically functional derivative thereof by facilitating prolongedrelease.
 14. The composition of claim 13, wherein the matrix-formingcompound is alginic acid and the bioadhseive compound is xanthan gum.15. The composition of claim 13, wherein the lactic acid is L-lacticacid.
 16. A composition comprising: (a) a matrix-forming compoundconsisting of alginic acid; (b) a bioadhesive compound consisting ofxanthan gum; (c) L-lactic acid; (d)1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid or aphysiologically functional derivative thereof; and (e) water.
 17. Thecomposition of claim 16, further comprising a humectant selected fromthe group consisting of: glycerol, polyethylene glycol, propyleneglycol, sorbitol, and tiracetin.
 18. The composition of claim 16,further comprising a preservative selected from the group consisting of:benzoic acid, sodium benzoate, methylparaben, ethylparaben,butylparaben, propylparaben, benzyalkonium chloride, phenylmercuricnitrate, and chlorhexidine.
 19. A composition comprising: (a) alginicacid; (b) xanthan gum; (c) L-lactic acid; (d) glycerol; (e) benzoicacid; (f) citric acid; (g) potassium bitartrate; (h)1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid or aphysiologically functional derivative thereof; and (i) water.
 20. Thecomposition of claim 1, wherein the the lactic acid is L-lactic acid andwherein the matrix forming compound and the bioadhseive compound isalginic acid.